Br J Clin Pharmacol (2016) 81 1002–1004
British Journal of Clinical Pharmacology
1002
LETTER TO THE EDITOR Reduction of hyperbilirubinemia with hypericum extract (St. John’s Wort) in a patient with Crigler-Najjar syndrome type II Correspondence Stephan Krähenbühl, MD, PhD, Division of Clinical Pharmacology & Toxicology, University Hospital, 4031 Basel, Switzerland. Tel.: +41 61 265 4715; Fax: +41 61 265 45 60; E-mail: [email protected]
Received 3 September 2015; revised 14 November 2015; accepted 29 November 2015
Oliver Kummer*, Felix Hammann*, Manuel Haschke and Stephan Krähenbühl Division of Clinical Pharmacology & Toxicology, University Hospital Basel and Department of Biomedicine, University of Basel, Switzerland *Oliver Kummer and Felix Hammann contributed equally to this work.
Keywords Crigler-Najjar syndrome, hyperbilirubinemia, hypericum, uridine 5′-diphospho-glucuronosyltransferase 1A1
AIMS Crigler-Najjar syndrome (CN) type II is a congenital disease with unconjugated hyperbilirubinemia due to a deficiency of uridine 5′-diphospho-glucuronosyltransferase 1A1. Since the currently proposed treatment with phenobarbital is associated with adverse reactions, we investigated the effect of hypericum extract.
METHODS Repetitive determination of total serum bilirubin in a female with CN type II before, during and after daily treatment with 900 mg hypericum extract on two occasions for 8 weeks. Confirmation of the enzyme-inducing effect of hypericum using the cytochrome P450 3A4 probe drug i.v. midazolam.
RESULTS Hypericum reduced midazolam exposure by 42% and the total serum bilirubin concentration by 30 to 35%.
CONCLUSIONS Hypericum extract is a potential alternative to phenobarbital in patients with CN type II.
Crigler-Najjar syndrome (CN) type II is characterized by congenital, nonhemolytic hyperbilirubinemia due to a defect of uridine 5′-diphospho-glucuronosyltransferase 1A1 (UGT1A1) [1]. Patients with CN type II have only a partial UGT1A1 deficiency and can be treated with phenobarbital, which induces UGT1A1 [1]. Treatment with phenobarbital is associated with adverse reactions, however, including sedation, depression, and teratogenicity [2]. Phenobarbital induces UGT1A1 via activation of the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) [3], which can also be activated by hyperforin, a constituent of hypericum extract © 2015 The British Pharmacological Society
[4]. Clofibrate is another treatment option [5], but there is less experience compared to phenobarbital. In addition, orlistat has been shown to decrease the serum bilirubin concentration in patients with CN treated with phenobarbital or phototherapy [6]. Since hypericum extracts containing the PXR inducer hyperforin are well-tolerated treatments for depression, we decided to treat a patient with CN type II with hypericum extract and to monitor her total serum bilirubin concentration. The study was approved by the local Ethics Committee and the patient, a non-smoking, jaundiced, but otherwise healthy, 24-year-old Caucasian woman without concomitant DOI:10.1111/bcp.12869
St. John’s Wort extract in Crigler-Najjar syndrome type II
medication, gave written informed consent. CN type II had been confirmed by point mutations in the nucleotide positions 211 and 1456 of the UGT1A1 gene. The patient was treated with 300 mg hypericum (St. John’s Wort) dry extract three times daily (Jarsin® LI160, Vifor SA, Switzerland; extract obtained using 80% methanol and standardized to 0.36–0.84 mg total hypericin per 300 mg dry extract) during two periods of eight weeks 18 months apart. PXR activation was assessed using the CYP3A4 probe drug midazolam (2 mg i.v. [Dormicum®, Hoffmann-LaRoche Ltd, Switzerland]) before and 3 weeks after starting hypericum extract [7]. During treatment, the patient reported feeling better with hypericum than without. On study days, specific questioning revealed less fatigue and an improved quality of life and clinical investigation revealed decreased jaundice. She described episodes of dyspepsia and facial skin prickling after outdoor activities. CYP3A4 induction by hypericum was confirmed by a 42% reduction in the AUC of i.v. midazolam (Figure 1A,B). Interestingly, hypericum extract was hitherto assumed to induce primarily intestinal CYP3A4 [8], with only few articles describing hepatic effects [9]. As parenteral administration of midazolam circumvents intestinal metabolism, our findings demonstrate that hepatic CYP3A4 can also be induced by hypericum extract. This is in line with work by Dresser et al. who showed a 1.5-fold increase in the clearance
of intravenous midazolam after treatment with hypericum extract [10]. Hypericum was associated with a drop in the average serum bilirubin concentration, reaching 34% compared to the mean basal concentration during the first (Figure 1C) and 31% during the second treatment period (Figure 1D). The effect on serum bilirubin was clearly detectable 2 weeks after starting (Figure 1C) and reversible later than 1 week after stopping treatment (Figure 1C,D). Similar to the current findings, phenobarbital decreased the bilirubin concentration in CN type II patients by approximately 40% [1]. Although patients can become tolerant to the sedative effect of phenobarbital, depression and teratogenicity can limit long-term treatment [2]. In comparison, common adverse effects of hypericum extract are dyspepsia, dizziness, and fatigue. Phototoxic skin reactions are associated with high hyperforin exposure [11], which is usually not reached with therapeutic doses of hypericum extract LI160. Although so far no major fetal malformations or adverse reactions in breastfed infants have been noted, the current safety data are not sufficient to consider hypericum extract a safe medication in pregnancy or lactation [12]. The antidepressive effect of hypericum extract may be an additional advantage of hypericum extract compared to other treatments in patients with CN type II. In conclusion, hypericum extract LI160 lowered the serum bilirubin concentrations in a patient with CN type II.
Figure 1 Effect of hypericum extract on midazolam exposure and serum bilirubin concentrations in a patient with Crigler-Najjar syndrome type II. The patient was treated with 900 mg hypericum extract per day for 8 weeks on 2 occasions 18 months apart (Figure 1C,D). Before and during the first treatment period, CYP3A4 activity was assessed by i.v. midazolam (Figure 1A,B). The dotted lines in Figure 1C,D indicate two standard deviations (SD) of the averaged serum bilirubin concentrations before treatment. See text for further explanations. Br J Clin Pharmacol (2016) 81 1002–1004
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O. Kummer et al.
Larger studies are needed, however, to prove the generalizability of this finding. Furthermore, we show that hypericum extract LI160 can also induce hepatic and not only intestinal CYP3A4.
Competing Interest All authors have completed the Unified Competing Interest form and received no support from any organization for the submitted work, had no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and had no other relationships or activities that could appear to have influenced the submitted work. This research received no specific funding.
References 1 Pett S, Mowat AP. Crigler-Najjar syndrome types I and II. Clinical experience–King’s College Hospital 1972–1978. Phenobarbitone, phototherapy and liver transplantation. Mol Aspects Med 1987; 9: 473–82. 2 Kwan P, Brodie MJ. Neuropsychological effects of epilepsy and antiepileptic drugs. Lancet 2001; 357: 216–22. 3 Wang H, LeCluyse EL. Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin Pharmacokinet 2003; 42: 1331–57. 4 Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL, Kliewer SA. St John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci U S A 2000; 97: 7500–2.
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Br J Clin Pharmacol (2016) 81 1002–1004
5 Schwegler U, May B, Muller KM. Crigler-Najjar syndrome type II in a 17-year-old girl. Z Gastroenterol 1993; 31: 83–4. 6 Hafkamp AM, Nelisse-Haak R, Sinaasappel M, Oude Elferink RP, Verkade HJ. Orlistat treatment of unconjugated hyperbilirubinemia in Crigler-Najjar disease: a randomized controlled trial. Pediatr Res 2007; 62: 725–30. 7 Link B, Haschke M, Wenk M, Krähenbühl S. Determination of midazolam and its hydroxy metabolites in human plasma and oral fluid by liquid chromatography/electrospray ionization ion trap tandem mass spectrometry. Rapid Commun Mass Spectrom 2007; 21: 1531–40. 8 Wang Z, Gorski JC, Hamman MA, Huang SM, Lesko LJ, Hall SD. The effects of St John’s wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 2001; 70: 317–26. 9 Lau WC, Welch TD, Shields T, Rubenfire M, Tantry US, Gurbel PA. The effect of St John’s wort on the pharmacodynamic response of clopidogrel in hyporesponsive volunteers and patients: increased platelet inhibition by enhancement of CYP3A4 metabolic activity. J Cardiovasc Pharmacol 2011; 57: 86–93. 10 Dresser GK, Schwarz UI, Wilkinson GR, Kim RB. Coordinate induction of both cytochrome P4503A and MDR1 by St John’s wort in healthy subjects. Clin Pharmacol Ther 2003; 73: 41–50. 11 Schempp CM, Winghofer B, Muller K, Schulte-Monting J, Mannel M, Schopf E, Simon JC. Effect of oral administration of Hypericum perforatum extract (St. John’s wort) on skin erythema and pigmentation induced by UVB, UVA, visible light and solar simulated radiation. Phytother Res 2003; 17: 141–6. 12 Dante G, Bellei G, Neri I, Facchinetti F. Herbal therapies in pregnancy: what works? Curr Opin Obstet Gynecol 2014; 26: 83–91.
British Journal of Clinical Pharmacology
1002
LETTER TO THE EDITOR Reduction of hyperbilirubinemia with hypericum extract (St. John’s Wort) in a patient with Crigler-Najjar syndrome type II Correspondence Stephan Krähenbühl, MD, PhD, Division of Clinical Pharmacology & Toxicology, University Hospital, 4031 Basel, Switzerland. Tel.: +41 61 265 4715; Fax: +41 61 265 45 60; E-mail: [email protected]
Received 3 September 2015; revised 14 November 2015; accepted 29 November 2015
Oliver Kummer*, Felix Hammann*, Manuel Haschke and Stephan Krähenbühl Division of Clinical Pharmacology & Toxicology, University Hospital Basel and Department of Biomedicine, University of Basel, Switzerland *Oliver Kummer and Felix Hammann contributed equally to this work.
Keywords Crigler-Najjar syndrome, hyperbilirubinemia, hypericum, uridine 5′-diphospho-glucuronosyltransferase 1A1
AIMS Crigler-Najjar syndrome (CN) type II is a congenital disease with unconjugated hyperbilirubinemia due to a deficiency of uridine 5′-diphospho-glucuronosyltransferase 1A1. Since the currently proposed treatment with phenobarbital is associated with adverse reactions, we investigated the effect of hypericum extract.
METHODS Repetitive determination of total serum bilirubin in a female with CN type II before, during and after daily treatment with 900 mg hypericum extract on two occasions for 8 weeks. Confirmation of the enzyme-inducing effect of hypericum using the cytochrome P450 3A4 probe drug i.v. midazolam.
RESULTS Hypericum reduced midazolam exposure by 42% and the total serum bilirubin concentration by 30 to 35%.
CONCLUSIONS Hypericum extract is a potential alternative to phenobarbital in patients with CN type II.
Crigler-Najjar syndrome (CN) type II is characterized by congenital, nonhemolytic hyperbilirubinemia due to a defect of uridine 5′-diphospho-glucuronosyltransferase 1A1 (UGT1A1) [1]. Patients with CN type II have only a partial UGT1A1 deficiency and can be treated with phenobarbital, which induces UGT1A1 [1]. Treatment with phenobarbital is associated with adverse reactions, however, including sedation, depression, and teratogenicity [2]. Phenobarbital induces UGT1A1 via activation of the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) [3], which can also be activated by hyperforin, a constituent of hypericum extract © 2015 The British Pharmacological Society
[4]. Clofibrate is another treatment option [5], but there is less experience compared to phenobarbital. In addition, orlistat has been shown to decrease the serum bilirubin concentration in patients with CN treated with phenobarbital or phototherapy [6]. Since hypericum extracts containing the PXR inducer hyperforin are well-tolerated treatments for depression, we decided to treat a patient with CN type II with hypericum extract and to monitor her total serum bilirubin concentration. The study was approved by the local Ethics Committee and the patient, a non-smoking, jaundiced, but otherwise healthy, 24-year-old Caucasian woman without concomitant DOI:10.1111/bcp.12869
St. John’s Wort extract in Crigler-Najjar syndrome type II
medication, gave written informed consent. CN type II had been confirmed by point mutations in the nucleotide positions 211 and 1456 of the UGT1A1 gene. The patient was treated with 300 mg hypericum (St. John’s Wort) dry extract three times daily (Jarsin® LI160, Vifor SA, Switzerland; extract obtained using 80% methanol and standardized to 0.36–0.84 mg total hypericin per 300 mg dry extract) during two periods of eight weeks 18 months apart. PXR activation was assessed using the CYP3A4 probe drug midazolam (2 mg i.v. [Dormicum®, Hoffmann-LaRoche Ltd, Switzerland]) before and 3 weeks after starting hypericum extract [7]. During treatment, the patient reported feeling better with hypericum than without. On study days, specific questioning revealed less fatigue and an improved quality of life and clinical investigation revealed decreased jaundice. She described episodes of dyspepsia and facial skin prickling after outdoor activities. CYP3A4 induction by hypericum was confirmed by a 42% reduction in the AUC of i.v. midazolam (Figure 1A,B). Interestingly, hypericum extract was hitherto assumed to induce primarily intestinal CYP3A4 [8], with only few articles describing hepatic effects [9]. As parenteral administration of midazolam circumvents intestinal metabolism, our findings demonstrate that hepatic CYP3A4 can also be induced by hypericum extract. This is in line with work by Dresser et al. who showed a 1.5-fold increase in the clearance
of intravenous midazolam after treatment with hypericum extract [10]. Hypericum was associated with a drop in the average serum bilirubin concentration, reaching 34% compared to the mean basal concentration during the first (Figure 1C) and 31% during the second treatment period (Figure 1D). The effect on serum bilirubin was clearly detectable 2 weeks after starting (Figure 1C) and reversible later than 1 week after stopping treatment (Figure 1C,D). Similar to the current findings, phenobarbital decreased the bilirubin concentration in CN type II patients by approximately 40% [1]. Although patients can become tolerant to the sedative effect of phenobarbital, depression and teratogenicity can limit long-term treatment [2]. In comparison, common adverse effects of hypericum extract are dyspepsia, dizziness, and fatigue. Phototoxic skin reactions are associated with high hyperforin exposure [11], which is usually not reached with therapeutic doses of hypericum extract LI160. Although so far no major fetal malformations or adverse reactions in breastfed infants have been noted, the current safety data are not sufficient to consider hypericum extract a safe medication in pregnancy or lactation [12]. The antidepressive effect of hypericum extract may be an additional advantage of hypericum extract compared to other treatments in patients with CN type II. In conclusion, hypericum extract LI160 lowered the serum bilirubin concentrations in a patient with CN type II.
Figure 1 Effect of hypericum extract on midazolam exposure and serum bilirubin concentrations in a patient with Crigler-Najjar syndrome type II. The patient was treated with 900 mg hypericum extract per day for 8 weeks on 2 occasions 18 months apart (Figure 1C,D). Before and during the first treatment period, CYP3A4 activity was assessed by i.v. midazolam (Figure 1A,B). The dotted lines in Figure 1C,D indicate two standard deviations (SD) of the averaged serum bilirubin concentrations before treatment. See text for further explanations. Br J Clin Pharmacol (2016) 81 1002–1004
1003
O. Kummer et al.
Larger studies are needed, however, to prove the generalizability of this finding. Furthermore, we show that hypericum extract LI160 can also induce hepatic and not only intestinal CYP3A4.
Competing Interest All authors have completed the Unified Competing Interest form and received no support from any organization for the submitted work, had no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and had no other relationships or activities that could appear to have influenced the submitted work. This research received no specific funding.
References 1 Pett S, Mowat AP. Crigler-Najjar syndrome types I and II. Clinical experience–King’s College Hospital 1972–1978. Phenobarbitone, phototherapy and liver transplantation. Mol Aspects Med 1987; 9: 473–82. 2 Kwan P, Brodie MJ. Neuropsychological effects of epilepsy and antiepileptic drugs. Lancet 2001; 357: 216–22. 3 Wang H, LeCluyse EL. Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. Clin Pharmacokinet 2003; 42: 1331–57. 4 Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL, Kliewer SA. St John’s wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci U S A 2000; 97: 7500–2.
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Br J Clin Pharmacol (2016) 81 1002–1004
5 Schwegler U, May B, Muller KM. Crigler-Najjar syndrome type II in a 17-year-old girl. Z Gastroenterol 1993; 31: 83–4. 6 Hafkamp AM, Nelisse-Haak R, Sinaasappel M, Oude Elferink RP, Verkade HJ. Orlistat treatment of unconjugated hyperbilirubinemia in Crigler-Najjar disease: a randomized controlled trial. Pediatr Res 2007; 62: 725–30. 7 Link B, Haschke M, Wenk M, Krähenbühl S. Determination of midazolam and its hydroxy metabolites in human plasma and oral fluid by liquid chromatography/electrospray ionization ion trap tandem mass spectrometry. Rapid Commun Mass Spectrom 2007; 21: 1531–40. 8 Wang Z, Gorski JC, Hamman MA, Huang SM, Lesko LJ, Hall SD. The effects of St John’s wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 2001; 70: 317–26. 9 Lau WC, Welch TD, Shields T, Rubenfire M, Tantry US, Gurbel PA. The effect of St John’s wort on the pharmacodynamic response of clopidogrel in hyporesponsive volunteers and patients: increased platelet inhibition by enhancement of CYP3A4 metabolic activity. J Cardiovasc Pharmacol 2011; 57: 86–93. 10 Dresser GK, Schwarz UI, Wilkinson GR, Kim RB. Coordinate induction of both cytochrome P4503A and MDR1 by St John’s wort in healthy subjects. Clin Pharmacol Ther 2003; 73: 41–50. 11 Schempp CM, Winghofer B, Muller K, Schulte-Monting J, Mannel M, Schopf E, Simon JC. Effect of oral administration of Hypericum perforatum extract (St. John’s wort) on skin erythema and pigmentation induced by UVB, UVA, visible light and solar simulated radiation. Phytother Res 2003; 17: 141–6. 12 Dante G, Bellei G, Neri I, Facchinetti F. Herbal therapies in pregnancy: what works? Curr Opin Obstet Gynecol 2014; 26: 83–91.
